Metabolic Mechanisms in Locus Coeruleus Neuron Vulnerability in Neurodegenerative Disease

PROJECT SUMMARY Locus coeruleus (LC) dysfunction and degeneration occurs early in Alzheimer’s Disease (AD). LC degeneration also occurs early in other AD-related neurogenerative disorders, including Down Syndrome (DS) and Parkinson’s Disease (PD). Substantial evidence links LC degeneration in these conditions with clinically meaningful measures of disease progression. While studies support mitochondrial and metabolic mechanisms causing LC vulnerability in AD and related neurodegenerative disease, the mechanisms are poorly understood. My laboratory has new, unique data demonstrating early and selective LC degeneration in a mouse mutant for the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2). While several mouse models for AD, DS and PD show LC dysfunction and degeneration, strikingly, the Gpt2-null mouse shows the earliest LC degeneration (by postnatal day 18) of any mouse mutant thus far described. Importantly, recent data also support a link between GPT2-mediated metabolism and AD. Therefore, the study of GPT2-mediated mechanisms in LC health and degeneration provides an important opportunity to understand mechanisms of early LC vulnerability with broad significance to AD and related neurodegenerative disorders. The overriding objective of this R01 application is to define early metabolic mechanisms of LC vulnerability in Gpt2-null mice, and also in AD and DS mouse models, across the lifespan, including in gene-by-environment (GXE) experiments using an extended wakefulness paradigm. Our central hypothesis is that the vulnerable LC – across neurodegeneration mouse models – will exhibit signatures of defective metabolic mechanisms that will be apparent early, prior to LC neuronal death. In Aim 1, we will define the transcriptomic and metabolomic signatures of vulnerable LC neurons in the Gpt2-null mouse and in AD and DS mouse models, preceding and during neuronal death. In Aim 2, we will determine the cell-type specific requirements for Gpt2 in LC through conditional mutagenesis of Gpt2 in LC noradrenergic neurons or in glia. Finally, in Aim 3, we will define the extent to which Gpt2 mutation (in the Gpt2 heterozygote, Gpt2+/-) enhances LC vulnerability in adult brain, using provocations such as an extended wakefulness paradigm, or mating the Gpt2+/- mutation to AD mouse models. Sleep is an important brain function regulated by LC that has been implicated in disease progression in AD. In our preliminary data, we observe accelerated LC degeneration in adult Gpt2+/- mutant brain after provocation using an extended-wakefulness paradigm. Overall, the research in this R01 application will have a sustained impact because our finding of early LC neurodegeneration in the Gpt2-null mouse represents an important opportunity to advance our understanding of the early metabolic mechanisms of vulnerability in LC neurons. Because metabolite supplements that augment these GPT2-mediated mechanisms are available, this research may lead to important new strategies for preventative treatments for LC degeneration in AD/ADRD.